- Email: [email protected]
How parasites tolerate their hosts
Br. vet..]. (1994). 150, 311
GUEST EDITORIAL H O W PARASITES TOLERATE THEIR H O S T S
Parasitic organisms, from viruses to complex metazoans have, over evolutionary time, co-evolved and adapted themselves to the host environment using a remarkable range of mechanisms. As the complexity of the parasite grows, the mechanisms used to ensure survival in a hostile environment are also complex. But they are also dynamic and a parasite can no longer be regarded as an inert organism, protected only by a tough surface insusceptible to enzyme attack. Many of the mechanisms of adaptation are based on enzymes and the potential use of these for diagnosis, as vaccines or targets for antiparasitic therapeutic c o m p o u n d s is explored in the review by D.P. I~lox in this issue of the BI~. Invasion of the host is clearly a critical and essential start to a parasite developmental cycle, being marked by hatching or excystation of d o r m a n t infective stages, followed by transport to a specific cell or organ for further development. The molecular basis of host parasite specificity, which for host and organ selection is very strict, is largely unknown but much of what is known entails enzyme interactions activated by signals unique to the host and the organ requirements of the parasite. Abrogation of these signals or the enzymes they induce, malay of which are some tbrm of aminopeptidase, may well be an avenue for future antiparasite development. ,Ma interesting recent example of this is the H11 microvillar protein of the gut of Haemonchus contortus which will induce a useful degree of protective immunity in sheep (Munn et aL, 1993). There have been a n u m b e r of previous reports of such enzyntes, associated with exsheathment of larval stages, being responsible for protective inamunity or acute allergic reactions resulting in the 'self cure' of nematode infections especially of the digestive tract (Stewart, 1955; Stromberg et al., 1977). Proteases of various specificities are used extensively by metazoan parasites to counteract host inamune attack mechanisms. A range of proteinases has been described whose fnnction is to degrade host protein, e.g. haemoglobin, for nntrition and other host proteins to assist in migration. In the case of Fasciola hepatica, a cathepsin L-like proteinase has been identified but its further activity is to split the Fc portion fi'om the Fab of the lgG~ molecule, a process of fabulation, thereby preventing host effector-cell attachment and the subsequent degranulation and release of toxic products from eosinophils and other cells (Smith et al., 1993). Similar proteases capable of cleaving host IgG have been identified in other laelminths (e.g. microfilariae of Dirofilmia immitis, Tamashiro et al., 1987) and recently a serine protease has been recognized in the migratory larval stage of the warble fly Hi,poderma lineal um which also cleaves bovine IgG into Fc and Fab 0007-1935/94/0,1 311-03/$08.00/0
© 1994 Bailli~reTindall
312
BRITISH VETERINARY JOURNAL, 150, 4
fragments (Pruett, 1993). The peptide fragments released from cleavage of immunoglobulin may function further to dampen down the host response by modifying macrophage function (Auriault et al., 1981), regulate the synthesis of IgE and inactivate complement (Leid et al., 1987). Even when immune aggressor cells do succeed in their kamikaze mission to deliver helminthotoxic products to a parasite, a range of parasite defence mechanisms are brought into effect. Examples are superoxide dismutase and glutathione peroxide neutralizing reactive oxygen intermediates produced by host effector cells, while glutathione transferases neun'alize or detoxify products of lipid membrane peroxidation (Brophy & Pritchard, 1992). Acetylcholinesterase has been detected in a range of parasitic helminths and various functions have been ascribed to it, but an important recent addition to these is that of immunomodulation through a breakdown of acetylcholine which is concerned with several immune effector mechanisms (McKeand et al., 1993). These various substances have been described as 'functional antigens' (Soulsby, 1962) i.e. serving as essential components of the parasites' physiological mechanisms, while also being putative antigens to induce protective immunity. Indeed their role in inducing protective immunity has been canvassed by many authors over the last two or three decades but the advent of molecular biological expression systems that now allow production of such functional antigens in large amounts should lead to a greater opportunity to develop effective sub-unit parasite vaccines. But such defence mechanisms and their components have the potential for other novel approaches to parasite control, one being their inhibition by chemical means and another in their use for diagnosis. The advent of monoclonal antibody technology offers the possibility of much more accurate diagnosis of parasite burdens by the detection and quantification of parasite enzymes in body fluids or faeces. Such tests would permit a more appropriate assessment of whether an animal should be treated with anthelmintics or not, thereby avoiding the unscientific approach of mass medication. Parasite enzymes must also be potential targets for new anthelmintics which would block development by interference with the signals leading to, for example, hatclaing and moulting. Such mechanisms are likely to be operative in the free-living stages of parasites, and the interference with developmental signals in pasture stages could result in marked reductions or even sterilization of the herbage. The availability of molecular, biological and transgenic technology make such approaches entirely feasible. LORDSOULSBV House of Lords London SW1A OPW
REFERENCES
AURbkULT,C., PasrEL,J.,JosEP., M., DESSAINT,j. P. & CAPRON,A. (1981). Interaction between macrophages and Schistosoma mansoni schistosomula: role of IgG peptides and aggregates
HOW PARASITES TOLERATE THEIR HOSTS
313
on the modulation of B-glucoronidase release and cytotoxicity against schistosomula. Cellularlmmunology 62, 15-27. BROPHV,P. M. & PPaTCrtaaD,D. I. (1992). Immunity to helminths: Ready to tip the biochemical balance? Parasitology Today 8, 419-21. KNOX, D. P. (1994). Parasite enzymes and the control of roundworm and fluke infestation in domestic animals. British VeterinaryJournal 150, 319-37. LEID, R. W., SUQUET,C. M. & TaNmOSm, L. (1987). Parasite defense mechanisms for the evasion of host attack: a review. Veterinary Parasitology 25, 147-62. McKmND, J. B., KNox, D. P., KENNEDY,M. W. & DUNCaN,J. L. (1993). The secretory acetylcholinesterases of Dictyocaulus viviparas. In Conference Handbook 14th International Conference of the WAAVP. p.106.8-13 August, 1993. MUNN, E. A., GRAHAM,M., SMITH,T. S., et al. (1993). Cloning, sequencing and expression of H11, a highly protective membrane protein antigen from Haemonchus contortus. In Conference Handbook 14th International Conference of the WAAVP. p. 109. 8-13 August, 1993. PRVE'rr,J. H. (1993). Proteolytic cleavage of bovine IgG by hypodermin A, a serine protease of Hypoderma linentum (Diptera: Oestridae).Journal of Parasitology 79, 829-33. SMITH,A. M., DOWD,A.J., HEFFERNAN,M., ROBERTSON,C. & D,'4.TON,J. P. (1993). Fasciola hepatica: a secreted cathepsin L-like proteinase cleaves host immunoglobulin. International Journal of Parasitology 23, 977-83. Sovussv, E . J . L . (1962). Antigen-antibody reactions in helminth infections. In Advances in Immunology, Vol. 2, eds W. H. Taliaferro &J. H. Humphrey, pp. 265-308. New York: Academic Press. STEWART,D. F. (1955). Self-cure in nematode infestations of sheep. Nature 176, 1273-4. STROMBER6, B. E., IZ~OURV,P. B. & SOULSSV,E . J . L . (1977). Ascaris suum immunisation with soluble antigens in the guinea pig. International Journal of Parasitology 7, 287-91. TAMASrURO,W. K., RAt, M. & Scoa-r, A. L. (1987). Proteolytic cleavage of IgG and other protein substrates by Dirofilaria immitis microfilarial enzymes. Journal of Parasitology 73, 149-54.
GUEST EDITORIAL H O W PARASITES TOLERATE THEIR H O S T S
Parasitic organisms, from viruses to complex metazoans have, over evolutionary time, co-evolved and adapted themselves to the host environment using a remarkable range of mechanisms. As the complexity of the parasite grows, the mechanisms used to ensure survival in a hostile environment are also complex. But they are also dynamic and a parasite can no longer be regarded as an inert organism, protected only by a tough surface insusceptible to enzyme attack. Many of the mechanisms of adaptation are based on enzymes and the potential use of these for diagnosis, as vaccines or targets for antiparasitic therapeutic c o m p o u n d s is explored in the review by D.P. I~lox in this issue of the BI~. Invasion of the host is clearly a critical and essential start to a parasite developmental cycle, being marked by hatching or excystation of d o r m a n t infective stages, followed by transport to a specific cell or organ for further development. The molecular basis of host parasite specificity, which for host and organ selection is very strict, is largely unknown but much of what is known entails enzyme interactions activated by signals unique to the host and the organ requirements of the parasite. Abrogation of these signals or the enzymes they induce, malay of which are some tbrm of aminopeptidase, may well be an avenue for future antiparasite development. ,Ma interesting recent example of this is the H11 microvillar protein of the gut of Haemonchus contortus which will induce a useful degree of protective immunity in sheep (Munn et aL, 1993). There have been a n u m b e r of previous reports of such enzyntes, associated with exsheathment of larval stages, being responsible for protective inamunity or acute allergic reactions resulting in the 'self cure' of nematode infections especially of the digestive tract (Stewart, 1955; Stromberg et al., 1977). Proteases of various specificities are used extensively by metazoan parasites to counteract host inamune attack mechanisms. A range of proteinases has been described whose fnnction is to degrade host protein, e.g. haemoglobin, for nntrition and other host proteins to assist in migration. In the case of Fasciola hepatica, a cathepsin L-like proteinase has been identified but its further activity is to split the Fc portion fi'om the Fab of the lgG~ molecule, a process of fabulation, thereby preventing host effector-cell attachment and the subsequent degranulation and release of toxic products from eosinophils and other cells (Smith et al., 1993). Similar proteases capable of cleaving host IgG have been identified in other laelminths (e.g. microfilariae of Dirofilmia immitis, Tamashiro et al., 1987) and recently a serine protease has been recognized in the migratory larval stage of the warble fly Hi,poderma lineal um which also cleaves bovine IgG into Fc and Fab 0007-1935/94/0,1 311-03/$08.00/0
© 1994 Bailli~reTindall
312
BRITISH VETERINARY JOURNAL, 150, 4
fragments (Pruett, 1993). The peptide fragments released from cleavage of immunoglobulin may function further to dampen down the host response by modifying macrophage function (Auriault et al., 1981), regulate the synthesis of IgE and inactivate complement (Leid et al., 1987). Even when immune aggressor cells do succeed in their kamikaze mission to deliver helminthotoxic products to a parasite, a range of parasite defence mechanisms are brought into effect. Examples are superoxide dismutase and glutathione peroxide neutralizing reactive oxygen intermediates produced by host effector cells, while glutathione transferases neun'alize or detoxify products of lipid membrane peroxidation (Brophy & Pritchard, 1992). Acetylcholinesterase has been detected in a range of parasitic helminths and various functions have been ascribed to it, but an important recent addition to these is that of immunomodulation through a breakdown of acetylcholine which is concerned with several immune effector mechanisms (McKeand et al., 1993). These various substances have been described as 'functional antigens' (Soulsby, 1962) i.e. serving as essential components of the parasites' physiological mechanisms, while also being putative antigens to induce protective immunity. Indeed their role in inducing protective immunity has been canvassed by many authors over the last two or three decades but the advent of molecular biological expression systems that now allow production of such functional antigens in large amounts should lead to a greater opportunity to develop effective sub-unit parasite vaccines. But such defence mechanisms and their components have the potential for other novel approaches to parasite control, one being their inhibition by chemical means and another in their use for diagnosis. The advent of monoclonal antibody technology offers the possibility of much more accurate diagnosis of parasite burdens by the detection and quantification of parasite enzymes in body fluids or faeces. Such tests would permit a more appropriate assessment of whether an animal should be treated with anthelmintics or not, thereby avoiding the unscientific approach of mass medication. Parasite enzymes must also be potential targets for new anthelmintics which would block development by interference with the signals leading to, for example, hatclaing and moulting. Such mechanisms are likely to be operative in the free-living stages of parasites, and the interference with developmental signals in pasture stages could result in marked reductions or even sterilization of the herbage. The availability of molecular, biological and transgenic technology make such approaches entirely feasible. LORDSOULSBV House of Lords London SW1A OPW
REFERENCES
AURbkULT,C., PasrEL,J.,JosEP., M., DESSAINT,j. P. & CAPRON,A. (1981). Interaction between macrophages and Schistosoma mansoni schistosomula: role of IgG peptides and aggregates
HOW PARASITES TOLERATE THEIR HOSTS
313
on the modulation of B-glucoronidase release and cytotoxicity against schistosomula. Cellularlmmunology 62, 15-27. BROPHV,P. M. & PPaTCrtaaD,D. I. (1992). Immunity to helminths: Ready to tip the biochemical balance? Parasitology Today 8, 419-21. KNOX, D. P. (1994). Parasite enzymes and the control of roundworm and fluke infestation in domestic animals. British VeterinaryJournal 150, 319-37. LEID, R. W., SUQUET,C. M. & TaNmOSm, L. (1987). Parasite defense mechanisms for the evasion of host attack: a review. Veterinary Parasitology 25, 147-62. McKmND, J. B., KNox, D. P., KENNEDY,M. W. & DUNCaN,J. L. (1993). The secretory acetylcholinesterases of Dictyocaulus viviparas. In Conference Handbook 14th International Conference of the WAAVP. p.106.8-13 August, 1993. MUNN, E. A., GRAHAM,M., SMITH,T. S., et al. (1993). Cloning, sequencing and expression of H11, a highly protective membrane protein antigen from Haemonchus contortus. In Conference Handbook 14th International Conference of the WAAVP. p. 109. 8-13 August, 1993. PRVE'rr,J. H. (1993). Proteolytic cleavage of bovine IgG by hypodermin A, a serine protease of Hypoderma linentum (Diptera: Oestridae).Journal of Parasitology 79, 829-33. SMITH,A. M., DOWD,A.J., HEFFERNAN,M., ROBERTSON,C. & D,'4.TON,J. P. (1993). Fasciola hepatica: a secreted cathepsin L-like proteinase cleaves host immunoglobulin. International Journal of Parasitology 23, 977-83. Sovussv, E . J . L . (1962). Antigen-antibody reactions in helminth infections. In Advances in Immunology, Vol. 2, eds W. H. Taliaferro &J. H. Humphrey, pp. 265-308. New York: Academic Press. STEWART,D. F. (1955). Self-cure in nematode infestations of sheep. Nature 176, 1273-4. STROMBER6, B. E., IZ~OURV,P. B. & SOULSSV,E . J . L . (1977). Ascaris suum immunisation with soluble antigens in the guinea pig. International Journal of Parasitology 7, 287-91. TAMASrURO,W. K., RAt, M. & Scoa-r, A. L. (1987). Proteolytic cleavage of IgG and other protein substrates by Dirofilaria immitis microfilarial enzymes. Journal of Parasitology 73, 149-54.